The field of the invention relates to compounds that selectively inactivate and/or inhibit Toxoplasma gondii ornithine aminotransferase (TgOAT). In particular, the field of the invention relates to selective inactivators and/or inhibitors of TgOAT for the treatment for the treatment of infection associated with Toxoplasma gondii and/or Plasmodium falciparum. 
Toxoplasmosis, the disease caused by the parasite Toxoplasma gondii (T. gondii), is the leading cause of death attributed to food-borne illness in the United States. It is estimated that this parasite infects between 30 and 50% of the world population. One potential therapeutic target in the fight against this parasite is ornithine aminotransferase (TgOAT), a pyridoxal 5′-phosphate (PLP)-dependent enzyme that plays a crucial role in preventing toxic accumulation of ornithine in the cell. A selective inhibition of OAT in T. gondii over human OAT is highly desired in either eliminating the growth of the parasites or preventing the shedding of long lived and persisting infectious oocysts into the environment. We have characterized a number of features of TgOAT: the gene, protein, abundance in different life cycle stages, and enzyme activity. A screening of our library of 23 GABA analogues resulted in several selective inactivators of TgOAT. Crystal structures of the native and inactivated enzymes were obtained. Two different inactivation mechanisms of two different inactivators were identified: one by gabaculine, which inactivated the enzyme by forming an aromatic ring inside the active site, which created a large energy barrier to reversal and put the product in a deep thermodynamic well, and the other by (S)-4-amino-5-fluoropentanoic acid, which inactivated the enzyme by forming a covalent adduct to the enzyme. These newly identified TgOAT inactivators and insights of the enzyme binding pocket from crystal structures lay a foundation of further studies of selective inactivation of TgOAT and drug development.